Abstract
We examined the effects of modulating group II metabotropic glutamate receptors (mGluRs) on traumatic neuronal injury using both in vitro and in vivo models. Treatment with various selective group II mGluR agonists significantly decreased lactate dehydrogenase release, a marker of cell death, after traumatic injury to rat neuronal-glial cultures; injury-induced increases in cyclic AMP and glutamate levels were also significantly reduced by a group II agonist. The neuroprotective effects of group II agonists were markedly attenuated by coadministration of a group II antagonist or a membrane-permeable cyclic AMP analog and were additive to those provided by anN-methyl-d-aspartate receptor antagonist or a selective group I mGluR antagonist. Administration of a group II mGluR agonist 30 min after lateral fluid percussion-induced brain injury in rats significantly improved subsequent behavioral recovery as compared with vehicle-treated controls. Together these studies indicate that group II mGluR agonists protect against traumatic neuronal injury by attenuating glutamate release and cAMP levels and suggest a potential role for these agents in the treatment of clinical neurotrauma.
Footnotes
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Send reprint requests to: A. I. Faden, EP-04 Research Building, 3970 Reservoir Road, N.W., Washington, D.C. 20007. E-mail: fadena{at}giccs.georgetown.edu
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↵1 This study was supported by a cooperative research agreement with Department of Defense Grant DAMD-17-93-V-3018 and National Institutes of Health NS 37313.
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↵2 Laboratory of Neuroscience, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
- Abbreviations:
- LDH
- lactate dehydrogenase
- mGluR
- metabotropic glutamate receptor
- TBI
- traumatic brain injury
- NMDAR
- N-methyl-d-aspartate receptor
- APDC
- (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate
- DIV
- days in vitro
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- AIDA
- (R,S)-1-aminoindan-1,5-dicarboxylic acid
- DCG-IV
- (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine
- MCCG
- (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine
- EGLU
- (2S)-_-ethylglutamic acid
- MK-801
- (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine
- LY354740
- (1S,2S,5R,6S)-2aminobicyclo[3.1.0]hexane-2,6-dicarboxylate
- 8-Br-cAMP
- adenosine 3′,5′-cyclic monophosphate, 8-bromo, sodium salt
- Received October 28, 1998.
- Accepted February 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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Group II Metabotropic Glutamate Receptor Activation Attenuates Traumatic Neuronal Injury and Improves Neurological Recovery after Traumatic Brain Injury
